Use of ADNP for the treatment of glaucomatous optic neuropathy

ABSTRACT

Methods for preventing and treating glaucomatous optic neuropathy using peptides derived from or related to Activity Dependent Neuroprotective Factor (ADNP) are disclosed.

[0001] This application is a continuation-in-part of U.S. Ser. No.09/921,029, filed Aug. 2, 2001, which claims priority from U.S.Provisional Application Serial No. 60/230,964 filed Sep. 7, 2000.

[0002] The present application is directed to the use of ActivityDependent Neuroprotective Protein (ADNP) for the treatment ofglaucomatous optic neuropathy.

BACKGROUND OF THE INVENTION

[0003] The glaucomas are a heterogeneous group of optic neuropathiescharacterized by the cupping of the optic nerve head, thinning of theretinal nerve fiber layer due to loss of retinal ganglion cells, andspecific pathogenetic changes in the visual field. Although elevatedintraocular pressure (IOP) is an important risk factor for thedevelopment of many common forms of glaucoma (Sommer et al. 1991), thephenomenon of normal tension glaucoma has been clinically established inophthalmology (Flammer 1990). Normal tension glaucoma is characterizedby an intraocular pressure which is in the normal range, i.e., notincreased, but in which the optic nerve disk is pathologically excavatedand the field of vision is impaired.

[0004] At the present time glaucoma, including normal tension glaucoma,is treated by medically and/or surgically lowering elevated pressure;however, even when IOP is maintained with in a normal range visual fieldloss may progress. Degeneration involving retinal ganglion cells may berelated to compression of the nerve fiber bundles, excitotoxicity,ischemia, or other as yet unrecognized causative factors. Thus, factorsother than IOP may play a role in determining both the occurrence andrate of progression of retinal ganglion cell death and subsequent visualfield loss.

[0005] Using laboratory models, including ischemia, optic nerve crush,optic nerve transection, and cultured retinal ganglion cells (Adachi etal. 1998; Yoles et al. 1998; Di Polo et al. 1998; Caprioli et al. 1996;Woldemussie et al. 1997), various pharmacological agents have beentested as potential neuroprotective approaches designed to reduceretinal ganglion cell loss. These approaches have suggested thatantagonism of excitotoxicity or supplementation of neurotrophic factorscan protect retinal ganglion cells from degeneration in animal models.The use of compounds capable of reducing glutamate toxicity (WO94/13275) and polyamine antagonists (U.S. Pat. No. 5,710,165) to protectretinal ganglion cells and reduce visual field loss associated withglaucoma have been disclosed. The protective effect of MK-801, aglutamate antagonist, in a rat model of ocular hypertension, wasreported. (Chaudhary et al. 1998).

[0006] Activity dependent neurotrophic factor (ADNF) is a glia-derivedprotein which has been found to be neuroprotective at femtomolarconcentrations. ADNF is both a regulator of activity dependent neuronalsurvival and a neuroprotectant (Gozes et al. 1997; Brenneman et al.1998; and WO 96/11948). Gozes, et al., also describe ADNF as protectiveagainst a broad range of toxins relative to Alzheimer's disease, humanimmunodeficiency virus (HIV), excitotoxicity, and electrical blockade.They propose the compound for development against neurodegeneration(Gozes et al. 1996). U.S. Pat. No. 5,767,240 discloses that ADNF proteinincreases survival of activity dependent spinal cord nerves and cerebralcortical nerves, and prevents neuronal cell death resulting from HIV. Arecent publication by Guo et al. (1999), discloses that certainneurotrophic factors, including ADNF, protect hippocampal neurons whichcontain presenilin-1 mutations from glutamate induced cytotoxicity. WO98/35042 discloses the use of ADNF III for conditions leading toneuronal cell death. ADNF III is a separate gene from ADNF having apredicted molecular weight of about 123 kDa and havingneurotrophic/neuroprotective activity (WO 01/09311; Gozes et al. 2000).ADNF III has also been referred to as activity dependent neuroprotectivefactor (ADNP). None of these references disclose or suggest the use ofADNF and related compounds for use in treating glaucoma.

[0007] ADNP is a glial mediator of vasoactive intestinal peptide(VIP)-associated neuroprotection (Gozes et al. 2000). It has beendisclosed for the treatment of neurological deficiencies and for theprevention of cell death associated with: gp 120, the envelope proteinfrom the human immunodeficiency virus (HIV), N-methyl-D-aspartic acid,tetrodotoxin, and β-amyloid peptide (WO 98/35042). Pathologies said tobenefit from the therapeutic applications set forth in WO 98/35042 areset forth on page 60 of the publication. Pathologies include retinalneuronal degeneration, but there is no characterization of which retinaldisease this compound might target. Glaucomatous optic neuropathy is notdisclosed.

SUMMARY OF THE INVENTION

[0008] The present invention overcomes these and other drawbacks of theprior art by providing, in one aspect, a method for treatingglaucomatous optic neuropathy by administering to a patient in needthereof a composition containing a pharmaceutically effective amount ofa peptide, polypeptide or protein including a sequence consisting of atleast 8 contiguous amino acids from SEQ ID NO:2. Preferably, the peptideor polypeptide includes the sequence as set forth in SEQ ID NO:4 or SEQID NO:8.

[0009] It will be understood that the phrase “at least 8 contiguousamino acids” includes all lengths of peptide or polypeptide that are 8amino acids in length or longer, up to the full length of the protein(SEQ ID NO:2). That is, it includes peptides that are 9, 10, 11, 12,etc., 20, 21, 22, 23, etc., 40, 41, 42, 43, etc. 100, 101, 102, etc.,150, 151, 152 amino acids etc. and so on up to the full length of theprotein (1102 amino acids in length).

[0010] In another aspect, the present invention provides a method fortreating glaucomatous optic neuropathy by administering to a patient inneed thereof a composition containing a pharmaceutically effectiveamount of a peptide, polypeptide or protein including a sequenceconsisting of a sequence as set forth in SEQ ID NO:3, SEQ ID NO:5, SEQID NO:6, or SEQ ID NO:7.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The following drawing forms part of the present specification andis included to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to thisdrawing in combination with the detailed description of specificembodiments presented herein.

[0012]FIG. 1 illustrates a comparison of the amino acid sequence of ADNPand ADNF III. As shown, the amino acid sequence of ADNP contains a 33amino acid insert that is not present in the sequence of ADNF III.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0013] Glaucoma is a heterogeneous group of optic neuropathies thatshare certain clinical features. The loss of vision in glaucoma is dueto the selective death of retinal ganglion cells in the neural retinathat is clinically diagnosed by characteristic changes in the visualfield, nerve fiber layer defects, and a progressive cupping of the ONH.One of the main risk factors for the development of glaucoma is thepresence of ocular hypertension (elevated intraocular pressure, IOP).IOP also appears to be involved in the pathogenesis of normal tensionglaucoma where patients have what is often considered to be normal IOP.The elevated IOP associated with glaucoma is due to elevated aqueoushumor outflow resistance in the trabecular meshwork (TM), a smallspecialized tissue located in the iris-corneal angle of the ocularanterior chamber. Glaucomatous changes to the TM include a loss in TMcells and the deposition and accumulation of extracellular debrisincluding plaque-like material. In addition, there also are changes thatoccur in the glaucomatous optic nerve head. In glaucomatous eyes, thereare morphological and mobility changes in ONH glial cells. In responseto elevated IOP and/or transient ischemic insults, there is a change inthe composition of the ONH extracellular matrix and alterations in theglial cell and retinal ganglion cell axon morphologies.

[0014] As with previously described ADNF I, ADNF III exhibits potentneuroprotective effects, with the EC₅₀ of such neuroprotective effectsbeing in the femtomolar range. Based on the recognized homology betweenADNF I and hsp60, a heat shock protein, and PIF1, a DNA repair protein,these two epitopes were utilized to prepare antibodies which, in turn,were used to screen a mouse cDNA expression library to identify the newneuroprotective polypeptide ADNP. Human ADNP has also been cloned. Thehuman nucleotide sequence of ADNP is set forth in SEQ ID NO:1 and theamino acid sequence is set forth in SEQ ID NO:2. It has been found thatthe amino acid sequence of ADNP contains a 33 amino acid insert (SEQ IDNO:9) as compared to the amino acid sequence of ADNF III. FIG. 1provides a comparison of the sequences of ADNF III and ADNP,illustrating the insert.

[0015] The present inventors have discovered that administering an ADNPpeptide or protein consisting of at least eight contiguous amino acidsfrom SEQ ID NO:2 provides a means for protection of both the retina andthe optic nerve/nerve head of glaucoma patients. Thus, ADNP is believedto be useful to treat glaucomatous optic neuropathy. As used herein ADNPmeans ADNP, ADNP peptides, ADNP peptidomimetics, ADNP small moleculeanalogues, and any agent that upregulates endogenous ADNP, or anexpression vector which induces ADNP expression.

[0016] Based on the homology between ADNF I and hsp60 to ANDP, apolypeptide consisting of eight contiguous amino acids of SEQ ID NO:2was synthesized that exhibited structural homology to hsp60 and to thepreviously described ADNF-derived active peptide SALLRSIPA (SEQ IDNO:3). This ADNP polypeptide is 8 amino acids in length and has thesequence NAPVSIPQ, i.e., Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:4).Other sequences contemplated to be useful in the practice of the presentinvention include sequences comprising any one of the followingsequences: GSALLRSIPA (SEQ ID NO:5), VLGGGSALLRSIPA (SEQ ID NO:6),VEEGIVLGGGSALLRSIPA (SEQ ID NO:7), TALLRTIPA (SEQ ID NO:8) and asequence essentially as set forth in SEQ ID NO:2.

[0017] The term “a sequence essentially as set forth in SEQ ID NO:2”means that the sequence substantially corresponds to a portion of SEQ IDNO:2 and has relatively few amino acids that are not identical to, or abiologically functional equivalent of, the amino acids of SEQ ID NO:2.The term “biologically functional equivalent” is well understood in theart. Accordingly, sequences that have between about 70% and about 80%;or more preferably, between about 81% and about 90%; or even morepreferably, between about 91% and about 99%; of amino acids that areidentical or functionally equivalent to the amino acids of SEQ ID NO:2will be sequences that are “essentially as set forth in SEQ ID NO: 1.”

[0018] It will also be understood that amino acid and nucleic acidsequences may include additional residues, such as additional N- orC-terminal amino acids or 5′ or 3′ sequences, and yet still beessentially as set forth in one of the sequences disclosed herein, solong as the sequence meets the criteria set forth above, including themaintenance of neuroprotective activity.

[0019] Thus, in one aspect, the present invention provides a method fortreating glaucomatous optic neuropathy by administering a compositionincluding a peptide or polypeptide consisting of at least 8 contiguousamino acids from SEQ ID NO:2. It is further contemplated that thecomposition could include a peptide comprising an amino acid sequence asset forth in SEQ ID NO:4, SEQ ID NO:8 or SEQ ID NO:9. It is alsocontemplated that the composition could include the full sequence ofADNP, as set forth in SEQ ID NO:2. In additional embodiments, thepresent invention provides a method for treating glaucomatous opticneuropathy by administering a composition including a peptide orpolypeptide consisting of SEQ ID NO: 3, SEQ ID NO:5, SEQ ID NO:6, or SEQID NO:7.

[0020] The agents of this invention, can be incorporated into varioustypes of ophthalmic formulations for delivery to the eye (e.g.,topically, intracamerally, or via an implant). The agents are preferablyincorporated into topical ophthalmic formulations for delivery to theeye. The agents may be combined with ophthalmologically acceptablepreservatives, surfactants, viscosity enhancers, penetration enhancers,buffers, sodium chloride, and water to form an aqueous, sterileophthalmic suspension or solution. Ophthalmic solution formulations maybe prepared by dissolving an agent in a physiologically acceptableisotonic aqueous buffer. Further, the ophthalmic solution may include anophthalmologically acceptable surfactant to assist in dissolving theagent. Furthermore, the ophthalmic solution may contain an agent toincrease viscosity, such as, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose,polyvinylpyrrolidone, or the like, to improve the retention of theformulation in the conjunctival sac. Gelling agents can also be used,including, but not limited to, gellan and xanthan gum. In order toprepare sterile ophthalmic ointment formulations, the active ingredientis combined with a preservative in an appropriate vehicle, such as,mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gelformulations may be prepared by suspending the agent in a hydrophilicbase prepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

[0021] The agents are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 4 to 8. The establishmentof a specific dosage regimen for each individual is left to thediscretion of the clinicians. The agents will normally be contained inthese formulations in an amount 0.01% to 5% by weight, but preferably inan amount of 0.05% to 2% and most preferably in an amount 0.1 to 1.0% byweight. The dosage form may be a solution, suspension microemulsion.Thus, for topical presentation 1 to 2 drops of these formulations wouldbe delivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

[0022] The agents can also be used in combination with other agents fortreating glaucoma, such as, but not limited to, β-blockers,prostaglandin analogs, carbonic anhydrase inhibitors, α₂ agonists,miotics, and neuroprotectants.

[0023] The agents can be administered in a variety of ways to achievetherapeutic concentrations at the retina and/or optic nerve head. Forexample, the agent may be delivered directly to the eye (for example:topical ocular drops or ointments; slow release devices in thecul-de-sac or implanted adjacent to the sclera or within the eye;periocular, conjunctival, sub-Tenons, intracameral or intravitrealinjections) or parenterally (for example: orally; intravenous,subcutaneous or intramuscular injections; dermal delivery; etc.) usingtechniques well known by those skilled in the art. The following areexamples of possible formulations embodied by this invention. (a)Topical ocular formulation wt. % ADNP peptide 0.005-5.0  Tyloxapol0.01-0.05 HPMC 0.5  Benalkonium chloride 0.01 Sodium chloride 0.8Edetate disodium 0.01 NaOH/HCl q.s. pH 7.4 Purified water q.s. 100 mL

[0024] It is further contemplated that the compounds of the inventioncould be formulated in intraocular insert devices.

[0025] All of the compositions and/or methods disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure. While the compositions and methods of thisinvention have been described in terms of preferred embodiments, it willbe apparent to those of skill in the art that variations may be appliedto the compositions and/or methods and in the steps or in the sequenceof steps of the method described herein without departing from theconcept, spirit and scope of the invention. More specifically, it willbe apparent that certain agents which are both chemically andstructurally related may be substituted for the agents described hereinto achieve similar results. All such substitutions and modificationsapparent to those skilled in the art are deemed to be within the spirit,scope and concept of the invention as defined by the appended claims.

[0026] References

[0027] The following references, to the extent that they provideexemplary procedural or other details supplementary to those set forthherein, are specifically incorporated herein by reference.

[0028] United States Patents

[0029] U.S. Pat. No. 5,710,165

[0030] U.S. Pat. No. 5,767,240

[0031] Foreign Patents and Published Patent Applications

[0032] WO 94/13275

[0033] WO 96/11948

[0034] WO 98/35042

[0035] WO 01/09311

[0036] Other Publications

[0037] Adachi, K. et al., Eur. J Pharmacol., 350:53-57 (1998).

[0038] Brenneman et al., JPET, 285:619-627 (1998).

[0039] Caprioli, J. et al., Invest. Ophthalmol. Vis. Sci., 37:2376-2381(1996).

[0040] Chaudhary, P. et al., Brain Res. 792:154-158 (1998).

[0041] Di Polo, A. et al., Proc. Natl. Acad. Sci, USA 95:3978-83 (1998).

[0042] Flammer, J., Fortschr. Ophthalmol. 87:187 (1990).

[0043] Gozes et al., Developmental Brain Research, 99(2):167-175 (1997).

[0044] Gozes et al., J. Molecular Neuroscience 7(4):235-244 (1996).

[0045] Gozes and Brenneman, J. Molecular Neuroscience 14:61-68 (2000).

[0046] Guo et al., Proc. Natl. Acad. Sci, 96:4125-4130 (1999).

[0047] Park et al., Biochem. Biophys. Res. Commun. 284(4):966-971(2001).

[0048] Sommer, A. et al., Arch. Ophthalmol. 109:1090-1095 (1991).

[0049] Woldemussie, E. et al., Invest. Ophthalmol. Vis. Sci., 38:S100(1997).

[0050] Yoles, E. et al., Arch. Opthalmol., 116:906-910 (1998).

1 9 1 4713 RNA homo sapiens 1 cggccgcggc gcgagccgga guccgccgagccggagcgcg acgaggcccc gggcgcgccc 60 uccccgcugc cgccaccgcc gugccgccgccauccgcccg ccgccgccgc cgcuguccgg 120 cccccgagca cgccggcccc gcgcgcgccucgaggccgag ucaaggugug agaugcacaa 180 ugcgaaaccu aggccccagc uuuuacaccaugaugcgcag gguuguacuu uuuguacuga 240 acugauaggu ggccuagugg uuaugcccuguacuaccauu uugaggaucu ggacuccguu 300 uccugccuug cucuuuggac cacauugucaauucacaccg aaacuauguu ccaacuuccu 360 gucaacaauc uuggcaguuu aagaaaagcccggaaaacug ugaaaaaaau acuuagugac 420 auuggguugg aauacuguaa agaacauauagaagauuuua aacaauuuga accuaaugac 480 uuuuauuuga aaaacacuac augggaggauguaggacugu gggacccauc acuuacgaaa 540 aaccaggacu aucggacaaa accuuucugcugcagcgcuu guccauuuuc cucaaaauuc 600 uucucugccu acaaaaguca uuuccgcaauguccauagug aagacuuuga aaauaggauu 660 cuccuuaauu gccccuacug uaccuucaaugcagacaaaa agacuuugga aacacacauu 720 aaaauauuuc augcuccgaa cgccagcgcaccaaguagca gccucagcac uuucaaagau 780 aaaaacaaaa augauggccu uaaaccuaagcaggcugaca guguagagca agcuguuuau 840 uacuguaaga agugcacuua ccgagauccucuuuaugaaa uaguuaggaa gcacauuuac 900 agggaacauu uucagcaugu ggcagcaccuuacauagcaa aggcaggaga aaaaucacuc 960 aauggggcag uccccuuagg cucgaaugcccgagaagaga guaguauuca cugcaagcga 1020 ugccuuuuca ugccaaaguc cuaugaagcuuugguacagc augucaucga agaccaugaa 1080 cguauaggcu aucaggucac ugccaugauugggcacacaa auguaguggu uccccgaucc 1140 aaacccuuga ugcuaauugc ucccaaaccucaagacaaga agagcauggg acucccacca 1200 aggaucgguu cccuugcuuc uggaaauguccggucuuuac caucacagca gauggugaau 1260 cgacucucaa uaccaaagcc uaacuuaaauucuacaggag ucaacaugau guccaguguu 1320 caucugcagc agaacaacua uggagucaaaucuguaggcc aggguuacag uguuggucag 1380 ucaaugagac ugggucuagg uggcaacgcaccaguuucca uuccucaaca aucucagucu 1440 guaaagcagu uacuuccaag uggaaacggaaggucuuaug ggcuuggguc agagcagagg 1500 ucccaggcac cagcaagaua cucccugcagucugcuaaug ccucuucucu cucaucgggc 1560 caguuaaagu cuccuucccu cucucagucacaggcaucca gaguguuagg ucaguccagu 1620 uccaaaccug cugcagcugc cacaggcccucccccaggua acacuuccuc aacucaaaag 1680 uggaaaauau guacaaucug uaaugagcuuuuuccugaaa augucuauag ugugcacuuc 1740 gaaaaagaac auaaagcuga gaaagucccagcaguagcca acuacauuau gaaaauacac 1800 aauuuuacua gcaaaugccu cuacuguaaucgcuauuuac ccacagauac ucugcucaac 1860 cauauguuaa uucauggucu gucuuguccauauugccguu caacuuucaa ugauguggaa 1920 aagauggccg cacacaugcg gaugguucacauugaugaag agaugggacc uaaaacagau 1980 ucuacuuuga guuuugauuu gacauugcagcaggguaguc acacuaacau ccaucuccug 2040 guaacuacau acaaucugag ggaugccccagcugaaucug uugcuuacca ugcccaaaau 2100 aauccuccag uuccuccaaa gccacagccaaagguucagg aaaaggcaga uaucccugua 2160 aaaaguucac cucaagcugc agugcccuauaaaaaagaug uugggaaaac ccuuuguccu 2220 cuuugcuuuu caauccuaaa aggacccauaucugaugcac uugcacauca cuuacgagag 2280 aggcaccaag uuauucagac gguucauccaguugagaaaa agcucaccua caaauguauc 2340 cauugccuug guguguauac cagcaacaugaccgccucaa cuaucacucu gcaucuaguu 2400 cacugcaggg gcguuggaaa gacccaaaauggccaggaua agacaaaugc acccucucgg 2460 cuuaaucagu cuccaagucu ggcaccugugaagcgcacuu acgagcaaau ggaauuuccc 2520 uuacugaaaa aacgaaaguu agaugaugauagugauucac ccagcuucuu ugaagagaag 2580 ccugaagagc cuguuguuuu agcuuuagaccccaaggguc augaagauga uuccuaugaa 2640 gccaggaaaa gcuuucuaac aaaguauuucaacaaacagc ccuaucccac caggagagaa 2700 auugagaagc uagcagccag uuuaugguuauggaagagug acaucgcuuc ccauuuuagu 2760 aacaaaagga agaagugugu ccgugauugugaaaaguaca agccuggcgu guugcugggg 2820 uuuaacauga aagaauuaaa uaaagucaagcaugagaugg auuuugaugc ugaguggcua 2880 uuugaaaauc augaugagaa ggauuccagagucaaugcua guaagacugc ugacaaaaag 2940 cucaaccuug ggaaggaaga ugacaguuccucagacaguu uugaaaauuu ggaagaagaa 3000 uccaaugaaa gugguagccc uuuugacccuguuuuugaag uugaaccuaa aaucucuaac 3060 gauaacccag aggaacaugu acugaagguaauuccugagg augcuucaga aucugaggag 3120 aagcuagacc aaaaagagga ugguucaaaauacgaaacua uucauuugac ugaggaacca 3180 accaaacuaa ugcacaaugc aucugauagugagguugacc aagacgaugu uguugagugg 3240 aaagacggug cuucuccauc ugagagugggccuggauccc aacaaguguc agacuuugag 3300 gacaauaccu gcgaaaugaa accaggaaccuggucugacg agucuuccca aagcgaagau 3360 gcaaggagca guaagccagc ugccaaaaaaaaggcuacca ugcaagguga cagagagcag 3420 uugaaaugga agaauaguuc cuauggaaaaguugaagggu uuuggucuaa ggaccaguca 3480 caguggaaga augcaucuga gaaugaugagcgcuuaucua acccccagau ugaguggcag 3540 aauagcacaa uugacaguga ggauggggaacaguuugaca acaugacuga uggaguagcu 3600 gagcccaugc auggcagcuu agccggaguuaaacugagca gccaacaggc cuaagugcca 3660 gguucccugg cauuggugac augcugcagccuggaacucu gaucuccagu gugacugcaa 3720 agcugucuuc ucacugguac ugccuugugaguacugguug gacugugggg cauguggccg 3780 cugcaguucc agugguuauu ucuaagucuaugacaggaca ggcuguucuu gcuucagaac 3840 cuucucugac agacacggua acuaaaugugaaaaaccaau aagcugguga cucaugaaua 3900 cacacgagga aaagcagagg uuuauuuuaucugccuuuuc aacauuucuu ucccucugug 3960 aaaugauugg ucagaugucu uugagaaguguuaaacuaau ucacauggua guguagggcc 4020 aacauacaag cuaccagucu aauguguauaguagacuuug ggaaaagcga uuuuuuuuca 4080 uguauucauu cugaauaguu gaaauguauauuuguacagu cuuuuagacc uauucaagug 4140 augcucauga uccuguuacu gugugcccaucauagauuuc uuuuuuuagu guugcccuug 4200 cuguguaaua aacgcucuau cuaguuuaccuagcaaaagc ucaaaacugc gcuaguaugg 4260 acuuuuugga cagacuuagu uuuugcacauaaccuuguac aaucuugcaa cagaggccag 4320 ccacguaaga uauauaucug gacucucuuguauuauagga uuuuucuugu ucugaauauc 4380 cuugacauua cagcugucaa aaacaaaaacugguauuuca gaucuguuuu cugaaaucuu 4440 uuaagcuaaa aucacaugca agaauugacuuugcagcuac uaauuuugac accuuuuaga 4500 ucuguauaaa aguguguugu guugaagcagcaaaccaaug agugcugcau uuuggauauu 4560 uaguuuuauc uuuaguucaa caccaucaugguggauucau uuauaccauc uaauauauga 4620 cacacuguug uaguauguau aauuuugugaucuuuauuuu cccuuuguau ucauuuuaag 4680 caucuaaaua aauugcugua uugugcuuaaugu 4713 2 1102 PRT homo sapiens 2 Met Phe Gln Leu Pro Val Asn Asn LeuGly Ser Leu Arg Lys Ala Arg 1 5 10 15 Lys Thr Val Lys Lys Ile Leu SerAsp Ile Gly Leu Glu Tyr Cys Lys 20 25 30 Glu His Ile Glu Asp Phe Lys GlnPhe Glu Pro Asn Asp Phe Tyr Leu 35 40 45 Lys Asn Thr Thr Trp Glu Asp ValGly Leu Trp Asp Pro Ser Leu Thr 50 55 60 Lys Asn Gln Asp Tyr Arg Thr LysPro Phe Cys Cys Ser Ala Cys Pro 65 70 75 80 Phe Ser Ser Lys Phe Phe SerAla Tyr Lys Ser His Phe Arg Asn Val 85 90 95 His Ser Glu Asp Phe Glu AsnArg Ile Leu Leu Asn Cys Pro Tyr Cys 100 105 110 Thr Phe Asn Ala Asp LysLys Thr Leu Glu Thr His Ile Lys Ile Phe 115 120 125 His Ala Pro Asn AlaSer Ala Pro Ser Ser Ser Leu Ser Thr Phe Lys 130 135 140 Asp Lys Asn LysAsn Asp Gly Leu Lys Pro Lys Gln Ala Asp Ser Val 145 150 155 160 Glu GlnAla Val Tyr Tyr Cys Lys Lys Cys Thr Tyr Arg Asp Pro Leu 165 170 175 TyrGlu Ile Val Arg Lys His Ile Tyr Arg Glu His Phe Gln His Val 180 185 190Ala Ala Pro Tyr Ile Ala Lys Ala Gly Glu Lys Ser Leu Asn Gly Ala 195 200205 Val Pro Leu Gly Ser Asn Ala Arg Glu Glu Ser Ser Ile His Cys Lys 210215 220 Arg Cys Leu Phe Met Pro Lys Ser Tyr Glu Ala Leu Val Gln His Val225 230 235 240 Ile Glu Asp His Glu Arg Ile Gly Tyr Gln Val Thr Ala MetIle Gly 245 250 255 His Thr Asn Val Val Val Pro Arg Ser Lys Pro Leu MetLeu Ile Ala 260 265 270 Pro Lys Pro Gln Asp Lys Lys Ser Met Gly Leu ProPro Arg Ile Gly 275 280 285 Ser Leu Ala Ser Gly Asn Val Arg Ser Leu ProSer Gln Gln Met Val 290 295 300 Asn Arg Leu Ser Ile Pro Lys Pro Asn LeuAsn Ser Thr Gly Val Asn 305 310 315 320 Met Met Ser Ser Val His Leu GlnGln Asn Asn Tyr Gly Val Lys Ser 325 330 335 Val Gly Gln Gly Tyr Ser ValGly Gln Ser Met Arg Leu Gly Leu Gly 340 345 350 Gly Asn Ala Pro Val SerIle Pro Gln Gln Ser Gln Ser Val Lys Gln 355 360 365 Leu Leu Pro Ser GlyAsn Gly Arg Ser Tyr Gly Leu Gly Ser Glu Gln 370 375 380 Arg Ser Gln AlaPro Ala Arg Tyr Ser Leu Gln Ser Ala Asn Ala Ser 385 390 395 400 Ser LeuSer Ser Gly Gln Leu Lys Ser Pro Ser Leu Ser Gln Ser Gln 405 410 415 AlaSer Arg Val Leu Gly Gln Ser Ser Ser Lys Pro Ala Ala Ala Ala 420 425 430Thr Gly Pro Pro Pro Gly Asn Thr Ser Ser Thr Gln Lys Trp Lys Ile 435 440445 Cys Thr Ile Cys Asn Glu Leu Phe Pro Glu Asn Val Tyr Ser Val His 450455 460 Phe Glu Lys Glu His Lys Ala Glu Lys Val Pro Ala Val Ala Asn Tyr465 470 475 480 Ile Met Lys Ile His Asn Phe Thr Ser Lys Cys Leu Tyr CysAsn Arg 485 490 495 Tyr Leu Pro Thr Asp Thr Leu Leu Asn His Met Leu IleHis Gly Leu 500 505 510 Ser Cys Pro Tyr Cys Arg Ser Thr Phe Asn Asp ValGlu Lys Met Ala 515 520 525 Ala His Met Arg Met Val His Ile Asp Glu GluMet Gly Pro Lys Thr 530 535 540 Asp Ser Thr Leu Ser Phe Asp Leu Thr LeuGln Gln Gly Ser His Thr 545 550 555 560 Asn Ile His Leu Leu Val Thr ThrTyr Asn Leu Arg Asp Ala Pro Ala 565 570 575 Glu Ser Val Ala Tyr His AlaGln Asn Asn Pro Pro Val Pro Pro Lys 580 585 590 Pro Gln Pro Lys Val GlnGlu Lys Ala Asp Ile Pro Val Lys Ser Ser 595 600 605 Pro Gln Ala Ala ValPro Tyr Lys Lys Asp Val Gly Lys Thr Leu Cys 610 615 620 Pro Leu Cys PheSer Ile Leu Lys Gly Pro Ile Ser Asp Ala Leu Ala 625 630 635 640 His HisLeu Arg Glu Arg His Gln Val Ile Gln Thr Val His Pro Val 645 650 655 GluLys Lys Leu Thr Tyr Lys Cys Ile His Cys Leu Gly Val Tyr Thr 660 665 670Ser Asn Met Thr Ala Ser Thr Ile Thr Leu His Leu Val His Cys Arg 675 680685 Gly Val Gly Lys Thr Gln Asn Gly Gln Asp Lys Thr Asn Ala Pro Ser 690695 700 Arg Leu Asn Gln Ser Pro Ser Leu Ala Pro Val Lys Arg Thr Tyr Glu705 710 715 720 Gln Met Glu Phe Pro Leu Leu Lys Lys Arg Lys Leu Asp AspAsp Ser 725 730 735 Asp Ser Pro Ser Phe Phe Glu Glu Lys Pro Glu Glu ProVal Val Leu 740 745 750 Ala Leu Asp Pro Lys Gly His Glu Asp Asp Ser TyrGlu Ala Arg Lys 755 760 765 Ser Phe Leu Thr Lys Tyr Phe Asn Lys Gln ProTyr Pro Thr Arg Arg 770 775 780 Glu Ile Glu Lys Leu Ala Ala Ser Leu TrpLeu Trp Lys Ser Asp Ile 785 790 795 800 Ala Ser His Phe Ser Asn Lys ArgLys Lys Cys Val Arg Asp Cys Glu 805 810 815 Lys Tyr Lys Pro Gly Val LeuLeu Gly Phe Asn Met Lys Glu Leu Asn 820 825 830 Lys Val Lys His Glu MetAsp Phe Asp Ala Glu Trp Leu Phe Glu Asn 835 840 845 His Asp Glu Lys AspSer Arg Val Asn Ala Ser Lys Thr Ala Asp Lys 850 855 860 Lys Leu Asn LeuGly Lys Glu Asp Asp Ser Ser Ser Asp Ser Phe Glu 865 870 875 880 Asn LeuGlu Glu Glu Ser Asn Glu Ser Gly Ser Pro Phe Asp Pro Val 885 890 895 PheGlu Val Glu Pro Lys Ile Ser Asn Asp Asn Pro Glu Glu His Val 900 905 910Leu Lys Val Ile Pro Glu Asp Ala Ser Glu Ser Glu Glu Lys Leu Asp 915 920925 Gln Lys Glu Asp Gly Ser Lys Tyr Glu Thr Ile His Leu Thr Glu Glu 930935 940 Pro Thr Lys Leu Met His Asn Ala Ser Asp Ser Glu Val Asp Gln Asp945 950 955 960 Asp Val Val Glu Trp Lys Asp Gly Ala Ser Pro Ser Glu SerGly Pro 965 970 975 Gly Ser Gln Gln Val Ser Asp Phe Glu Asp Asn Thr CysGlu Met Lys 980 985 990 Pro Gly Thr Trp Ser Asp Glu Ser Ser Gln Ser GluAsp Ala Arg Ser 995 1000 1005 Ser Lys Pro Ala Ala Lys Lys Lys Ala ThrMet Gln Gly Asp Arg 1010 1015 1020 Glu Gln Leu Lys Trp Lys Asn Ser SerTyr Gly Lys Val Glu Gly 1025 1030 1035 Phe Trp Ser Lys Asp Gln Ser GlnTrp Lys Asn Ala Ser Glu Asn 1040 1045 1050 Asp Glu Arg Leu Ser Asn ProGln Ile Glu Trp Gln Asn Ser Thr 1055 1060 1065 Ile Asp Ser Glu Asp GlyGlu Gln Phe Asp Asn Met Thr Asp Gly 1070 1075 1080 Val Ala Glu Pro MetHis Gly Ser Leu Ala Gly Val Lys Leu Ser 1085 1090 1095 Ser Gln Gln Ala1100 3 9 PRT homo sapiens 3 Ser Ala Leu Leu Arg Ser Ile Pro Ala 1 5 4 8PRT homo sapiens 4 Asn Ala Pro Val Ser Ile Pro Gln 1 5 5 10 PRT homosapiens 5 Gly Ser Ala Leu Leu Arg Ser Ile Pro Ala 1 5 10 6 14 PRT homosapiens 6 Val Leu Gly Gly Gly Ser Ala Leu Leu Arg Ser Ile Pro Ala 1 5 107 19 PRT homo sapiens 7 Val Glu Glu Gly Ile Val Leu Gly Gly Gly Ser AlaLeu Leu Arg Ser 1 5 10 15 Ile Pro Ala 8 9 PRT homo sapiens 8 Thr Ala LeuLeu Arg Thr Ile Pro Ala 1 5 9 33 PRT homo sapiens 9 Ser Thr Leu Ser PheAsp Leu Thr Leu Gln Gln Gly Ser His Thr Asn 1 5 10 15 Ile His Leu LeuVal Thr Thr Tyr Asn Leu Arg Asp Ala Pro Ala Glu 20 25 30 Ser

We claim:
 1. A method for treating glaucomatous optic neuropathy, saidmethod comprising administering to a patient in need thereof acomposition comprising a pharmaceutically effective amount of a peptideor protein comprising a sequence consisting of at least 8 contiguousamino acids from SEQ ID NO:2.
 2. The method of claim 1, wherein thepeptide comprises SEQ ID NO:4.
 3. The method of claim 1, wherein thecomposition comprises a peptide comprising a sequence consisting of atleast 9 contiguous amino acids from SEQ ID NO:2.
 4. The method of claim3, wherein the peptide comprises SEQ ID NO:8.
 5. A method for treatingglaucomatous optic neuropathy, said method comprising administering to apatient in need thereof a composition comprising a pharmaceuticallyeffective amount of a peptide or protein comprising a sequenceconsisting of a sequence selected from the group consisting of SEQ IDNO:3, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7.